Our overall aim is to determine the molecular mechanisms of [unreadable]-amyloid (A[unreadable])-induced synaptic loss and neuronal death. Deposition of insoluble A[unreadable], together with tangle formation, loss of synapses and neurons, are hallmarks of Alzheimer[unreadable]s disease. More recently soluble A[unreadable] oligomeric species have been found in AD and these may correlate with synaptic loss. While the debate continues about the role of each of these in the disease it is important to develop model systems where these processes can be studied. Studies show that increased A[unreadable] induces synaptotoxicity, a parameter which correlates with cognitive decline in AD. Evidence from our work and from other laboratories shows that aggregated and oligomeric A[unreadable] induce apoptosis in cultured neurons and that sublethal concentrations of A[unreadable] induce changes in synapse morphology in primary neurons and brain slices. Our work shows that A[unreadable] induces activation of caspase-2 and -3 but that only caspase-2 executes death. Caspase-2 and its downstream target Bim are increased in AD brains. We are proposing that, in neurons exposed to A[unreadable], the main function of caspase-3 is the regulation of synaptic plasticity, not the execution of cell death; caspase-2 executes death. We propose the hypothesis that there is dose-dependent activation of different caspases by A[unreadable] leading to synaptic remodeling, synaptic loss and neuronal death. Sublethal doses of A[unreadable] activate caspase-3; caspase-3 in this setting does not execute death but is responsible for remodeling synapses as a protective mechanism in response to A[unreadable]; the activity of caspase-3 is modulated by IAPs. With increasing time of exposure or increasing levels of A[unreadable], synapse pruning becomes excessive, leading to synaptotoxicity which in turn induces trophic factor deprivation leading to further synaptic loss and eventually to activation of caspase-2 and neuronal death. Lethal doses of A[unreadable] activate caspase-2 and caspase-3; caspase-2 induces Bim and executes the neuron, caspase-3 activity is inhibited from executing death by cIAP1. Different complexes serve to regulate caspase-2 activity in neurons. Caspase-2 activation requires RAIDD; PIDD complexes with RAIDD in healthy neurons to prevent caspase-2 activation. We will examine these hypotheses using primary hippocampal neuron cultures and mouse models of neurodegeneration, with the following specific aims: 1. To determine how caspases regulate synaptic loss induced by A[unreadable]. 2: To determine how caspases are regulated and activated by A[unreadable] and TFD. 3: To determine how caspase-2 regulates the induction of Bim after A[unreadable] treatment.